Adenosine is an ubiquitous modulator of numerous physiological activities, particularly within the cardiovascular and nervous systems. The effects of adenosine appear to be mediated by specific cell surface receptor proteins. Adenosine modulates diverse physiological functions including induction of sedation, vasodilation, suppression of cardiac rate and contractility, inhibition of platelet aggregability, stimulation of gluconeogenesis and inhibition of lipolysis. In addition to its effects on adenylate cyclase, adenosine has been shown to open potassium channels, reduce flux through calcium channels, and inhibit or stimulate phosphoinositide turnover through receptor-mediated mechanisms (See for example, C. E. Muller and B. Stein “Adenosine Receptor Antagonists: Structures and Potential Therapeutic Applications,” Current Pharmaceutical Design, 2:501 (1996) and C. E. Muller “A1-Adenosine Receptor Antagonists,” Exp. Opin. Ther. Patents 7(5):419 (1997)).
Adenosine receptors belong to the superfamily of purine receptors which are currently subdivided into P1 (adenosine) and P2 (ATP, ADP, and other nucleotides) receptors. Four receptor subtypes for the nucleoside adenosine have been cloned so far from various species including humans. Two receptor subtypes (A1 and A2a) exhibit affinity for adenosine in the nanomolar range while two other known subtypes A2b and A3 are low-affinity receptors, with affinity for adenosine in the low-micromolar range. A1 and A3 adenosine receptor activation can lead to an inhibition of adenylate cyclase activity, while A2a and A2b activation causes a stimulation of adenylate cyclase.
A few A1 antagonists have been developed for the treatment of cognitive disease, renal failure, and cardiac arrhythmias. It has been suggested that A2a antagonists may be beneficial for patients suffering from Morbus Parkinson (Parkinson's disease). Particularly in view of the potential for local delivery, adenosine receptor antagonists may be valuable for treatment of allergic inflammation and asthma. Available information (for example, Nyce & Metzger “DNA antisense Therapy for Asthma in an Animal Model” Nature (1997) 385: 721-5)indicates that in this pathophysiologic context, A1 antagonists may block contraction of smooth muscle underlying respiratory epithelia, while A2b or A3 receptor antagonists may block mast cell degranulation, mitigating the release of histamine and other inflammatory mediators. A2b receptors have been discovered throughout the gastrointestinal tract, especially in the colon and the intestinal epithelia. It has been suggested that A2b receptors mediate cAMP response (Strohmeier et al., J. Bio. Chem. (1995) 270:2387-94).
Adenosine receptors have also been shown to exist on the retinas of various mammalian species including bovine, porcine, monkey, rat, guinea pig, mouse, rabbit and human (See, Blazynski et al., “Discrete Distributions of Adenosine Receptors in Mammalian Retina,” Journal of Neurochemistry, volume 54, pages 648-655 (1990); Woods et al., “Characterization of Adenosine A1-Receptor Binding Sites in Bovine Retinal Membranes,” Experimental Eye Research, volume 53, pages 325-331 (1991); and Braas et al., “Endogenous adenosine and adenosine receptors localized to ganglion cells of the retina,” Proceedings of the National Academy of Science, volume 84, pages 3906-3910 (1987)). Recently, Williams reported the observation of adenosine transport sites in a cultured human retinal cell line (Williams et al., “Nucleoside Transport Sites in a Cultured Human Retinal Cell Line Established By SV-40 T Antigen Gene,” Current Eye Research, volume 13, pages 109-118 (1994)).
Compounds which regulate the uptake of adenosine have previously been suggested as potential therapeutic agents for the treatment of retinal and optic nerve head damage. In U.S. Pat. No. 5,780,450 to Shade, Shade discusses the use of adenosine uptake inhibitors for treating eye disorders. Shade does not disclose the use of specific A3 receptor inhibitors. The entire contents of U.S. Pat. No. 5,780,450 are hereby incorporated herein by reference.
Additional adenosine receptor antagonists are needed as pharmacological tools and are of considerable interest as drugs for the above-referenced disease states and/or conditions.